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Abstract

Checkpoint blockade immunotherapies enable the host immune system to recognize and destroy tumour cells1. Their clinical activity has been correlated with activated T-cell recognition of neoantigens, which are tumour-specific, mutated peptides presented on the surface of cancer cells2,3. Here we present a fitness model for tumours based on immune interactions of neoantigens that predicts response to immunotherapy. Two main factors determine neoantigen fitness: the likelihood of neoantigen presentation by the major histocompatibility complex (MHC) and subsequent recognition by T cells. We estimate these components using the relative MHC binding affinity of each neoantigen to its wild type and a nonlinear dependence on sequence similarity of neoantigens to known antigens. To describe the evolution of a heterogeneous tumour, we evaluate its fitness as a weighted effect of dominant neoantigens in the subclones of the tumour. Our model predicts survival in anti-CTLA-4-treated patients with melanoma4,5 and anti-PD-1-treated patients with lung cancer6. Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies. By using an immune fitness model to study immunotherapy, we reveal broad similarities between the evolution of tumours and rapidly evolving pathogens7,8,9.

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Contributions

M.Ł. and B.D.G. designed the mathematical model, analysed data and wrote the manuscript with critical comments from all the authors. N.R., V.M., V.P.B., M.D.H., A.S., N.A.R., T.M., A.J.L., T.A.C. and J.D.W. contributed to data acquisition and analysis. M.Ł., T.A.C., J.D.W. and B.D.G. contributed to study conception and design. M.Ł., N.R., V.M., V.P.B., M.D.H., A.S., N.A.R., T.M., A.J.L., T.A.C., J.D.W. and B.D.G. interpreted the data and provided a critical reading of the manuscript.

Competing interests

M.Ł. has consulted for Merck. V.P.B. has received research funding from Bristol-Myers Squibb. A.J.L. is on the board of directors for Adaptive Biotechnologies and has consulted for Jansen Pharmaceuticals and Merck. T.A.C. is a co-founder of Gritstone Oncology and holds equity. T.A.C. receives grant funding from Bristol Myers Squibb. N.A.R is co-founder and shareholder of Gritstone Oncology. M.D.H. has consulted for Genentech, BMS, Merck, AstraZeneca, Janssen and Novartis. B.D.G. has consulted for Merck.

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Editorial Summary

Predicting tumour response to immunotherapy

Response to immune checkpoint blockade is likely to depend on tumour-intrinsic and microenvironmental factors, and to be evolutionarily shaped by immune interactions. Marta uksza et al. use mathematical tumour fitness models adapted from infectious disease models as a framework for tumour-immune interactions. When applied to human melanoma and non-small-cell lung cancer data, the model can recreate the evolutionary dynamics of cancer cells under immune checkpoint blockade.